Murine models of human carcinogenesis are widely used to delineate genetic mechanisms that determine tumor initiation and progression and improved methods for genetic manipulation open new avenues to study biological pathways of tumorigenesis. We have therefore devoted considerable effort to the development of molecular cytogenetic tools for the analyses of chromosomal aberrations in mouse models of human cancer. Karyotype analysis of chemically induced plasmacytomas in mice, and in lymphomas from ATM or Ku80 deficient animals. These analyses helped to define genetic pathways involved in the maintenance of chromosomal integrity and elucidated mechanisms that contribute to chromosomal translocations, e.g., break induced replication. As part of the intramural mouse models of mammary cancer consortium (MMMC), we have analyzed a plethora of mammary gland adenocarcinomas (MMTC-c-myc, MMTV-her2neu, her2neu-ednogeneous promoter, C3SV40Tag, PyV-mT). These analyses have provided evidence for the conservation of mechanisms leading to chromosomal aberrations and to the maintenance of cancer specific patterns of chromosomal aneuploidies across species boundaries. Our development of molecular cytogenetic methods for the analysis of murine genomes allows us to further contribute to the validation of mouse models of human cancers. The analysis of the PyV-mT mouse model also resulted in the molecular cloning of a septin 9 as a novel oncogene involved in human breast cancers and mouse models thereof.In addition to the use of genetically engineered mice as model systems of human cancer, we have also developed cell lines from several different epithelial organs from normal mice, including cervix, mammary gland, and colon. After having overcome senescence, these cells become immortalized, transformed, and eventually can form tumors in nude mice. The careful molecular characterization of these steps using chromosomal analysis by SKY, high-resolution mapping of genomic imbalances using arrayCGH, determination of transcriptional alterations by expression profiling, and cell biological tests for the integrity of centrosomes and telomeres now allow establishing a precise and comprehensive sequence of events. These analyses suggest that the process of spontaneous transformation of murine epithelial cells mimics in many aspects changes during human tumorigenesis. We have therefore developed valuable tools to not only study multiple aspects of the sequential changes during carcinogenesis, but to also functionally characterize novel signaling pathways. The modification of these pathways will eventually point to relevant targets for therapeutic intervention in human cancer.